Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CEP-7055, a fully synthetic, orally active N,N-dimethylglycine ester of CEP-5214, a C3-(isopropylmethoxy)-fused pyrrolocarbazole with potent pan-vascular endothelial growth factor receptor (VEGFR) kinase inhibitory activity, has recently completed phase I clinical trials in cancer patients. These studies evaluated the antitumor efficacy of CEP-7055 using orthotopic models of glioblastoma and colon carcinoma in combination with temozolomide, and irinotecan and oxaliplatin, respectively, for their effects on primary and metastatic tumor burden and median survival. Chronic administration of CEP-7055 (23.8 mg/kg/dose) and temozolomide resulted in improvement of median survival of nude mice bearing orthotopic human glioblastoma xenografts compared with temozolomide alone (261 versus 192 days, respectively; P < or = 0.02). Reductions in neurologic dysfunction, brain edema, hemorrhage, and intratumoral microvessel density (CD34 staining) were observed in glioma-bearing mice receiving CEP-7055 alone, temozolomide alone, and the combination of CEP-7055 and temozolomide relative to vehicle and to temozolomide monotherapy. The administration of CEP-7055 in combination with irinotecan (20 mg/kg/dose i.p. x 5 days), and to a lesser degree with oxaliplatin (10 mg/kg/dose i.v.), showed reductions on primary colon carcinoma and hepatic metastatic burden in the CT-26 tumor model relative to that achieved by irinotecan and oxaliplatin monotherapy. These data show the significant efficacy and tolerability of optimal efficacious doses of CEP-7055 when given in combination with temozolomide and irinotecan relative to monotherapy with these cytotoxic agents in preclinical orthotopic glioma and colon carcinoma models and lend support for the use of these treatment regimens in a clinical setting in patients with glioblastoma and colon carcinoma.
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PMID:The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice. 1689 60

The effect of the potent and selective poly(ADP-ribose) (PAR) polymerase-1 [and PAR polymerase-2] inhibitor CEP-8983 on the ability to sensitize chemoresistant glioblastoma (RG2), rhabdomyosarcoma (RH18), neuroblastoma (NB1691), and colon carcinoma (HT29) tumor cells to temozolomide- and camptothecin-induced cytotoxicity, DNA damage, and G(2)-M arrest and on the potentiation of chemotherapy-induced myelotoxicity was evaluated using in vitro assays. In addition, the effect of the prodrug CEP-9722 in combination with temozolomide and/or irinotecan on PAR accumulation and tumor growth was also determined using glioblastoma and/or colon carcinoma xenografts relative to chemotherapy alone. CEP-8983 sensitized carcinoma cells to the growth-inhibitory effects of temozolomide and/or SN38 increased the fraction of and/or lengthened duration of time tumor cells accumulated in chemotherapy-induced G(2)-M arrest and sensitized tumor cells to chemotherapy-induced DNA damage and apoptosis. A granulocyte-macrophage colony-forming unit colony formation assay showed that coincubation of CEP-8983 with temozolomide or topotecan did not potentiate chemotherapy-associated myelotoxicity. CEP-9722 (136 mg/kg) administered with temozolomide (68 mg/kg for 5 days) or irinotecan (10 mg/kg for 5 days) inhibited significantly the growth of RG2 tumors (60%) or HT29 tumors (80%) compared with temozolomide or irinotecan monotherapy, respectively. In addition, CEP-9722 showed "stand alone" antitumor efficacy in these preclinical xenografts. In vivo biochemical efficacy studies showed that CEP-9722 attenuated PAR accumulation in glioma xenografts in a dose- and time-related manner. These data indicate that CEP-8983 and its prodrug are effective chemosensitizing agents when administered in combination with select chemotherapeutic agents against chemoresistant tumors.
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PMID:The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. 1769 24

CEP-1347 is a mixed lineage kinase inhibitor tested in a large-scale phase 2/3 clinical trial in early Parkinson's disease, in which its safety and tolerability, but nevertheless not efficacy, was demonstrated. Here we identify by drug repositioning CEP-1347 as a potential anti-cancer stem cell drug. In vitro, CEP-1347 efficiently induced differentiation and inhibited the self-renewal and tumor-initiating capacities of human cancer stem cells from glioblastoma as well as from pancreatic and ovarian cancers at clinically-relevant concentrations, without impairing the viability of normal fibroblasts and neural stem cells. In vivo, a 10-day systemic administration of CEP-1347 at a dose that was less than 1/10 the mouse equivalent of the dose safely given to humans for 2 years was sufficient to effectively reduce tumor-initiating cancer stem cells within established tumors in mice. Furthermore, the same treatment protocol significantly extended the survival of mice receiving orthotopic implantation of glioma stem cells. Together, our findings suggest that CEP-1347 is a promising candidate for cancer stem cell-targeting therapy and that further clinical and preclinical studies are warranted to evaluate its efficacy in cancer treatment.
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PMID:Repositioning CEP-1347, a chemical agent originally developed for the treatment of Parkinson's disease, as an anti-cancer stem cell drug. 2921 73

Human glioma is one of the major malignancies worldwide with an increased mortality rate. Centrosomal protein of 55 kDa (CEP55) is an essential component of the CEP family and has been identified as a prognostic marker for multiple types of cancer. However, the function of CEP55 during glioma tumorigenesis remains unclear. In the present study, the data derived from the Oncomine database indicated that the expression of CEP55 is increased in glioma tissues compared with normal tissues. Furthermore, the expression of CEP55 was also increased at the level of mRNA and protein in glioma cell lines compared with normal human astrocytes. The knockdown of CEP55 expression inhibited the proliferation of glioma U251 cells, whereas overexpression of CEP55 induced the proliferation of U251 cells. Flow cytometric analysis indicated that the knockdown of CEP55 resulted in an increased number of cells arrested at G2/M phase, and apoptosis was promoted. Further investigations revealed that the overexpression of CEP55 increased the phosphorylation of Akt and inhibited the activity of p21. By contrast, the knockdown of CEP55 resulted in the opposite effects. Taken together, the results of the present study suggested that CEP55 regulated the proliferation of glioma cells, further attributing to the carcinogenesis and progression of glioma via the PI3K/Akt/p21 signaling pathway. Therefore, CEP55 may be a novel therapeutic target for the treatment of glioma.
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PMID:CEP55 promotes cell proliferation and inhibits apoptosis via the PI3K/Akt/p21 signaling pathway in human glioma U251 cells. 2955 18

Lestaurtinib, also called CEP-701, is an inhibitor of tyrosine kinase, causes haematological remission in patients with AML possessing FLT3-ITD (FLT3 gene) internal tandem duplication and strongly inhibits tyrosine kinase FLT3. Treatment with lestaurtinib modulates various signalling pathways and leads to cell growth arrest and programmed cell death in several tumour types. However, the effect of lestaurtinib on glioma remains unclear. In this study, we examined lestaurtinib and TRAIL interactions in glioma cells and observed their synergistic activity on glioma cell apoptosis. While U87 and U251 cells showed resistance to TRAIL single treatment, they were sensitized to apoptosis induced by TRAIL in the presence of lestaurtinib because of increased death receptor 5 (DR5) levels through CHOP-dependent manner. We also demonstrated using a xenograft model of mouse that the tumour growth was absolutely suppressed because of the combined treatment compared to TRAIL or lestaurtinib treatment carried out singly. Our findings reveal a potential new strategy to improve antitumour activity induced by TRAIL in glioma cells using lestaurtinib through a mechanism dependent on CHOP.
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PMID:Lestaurtinib potentiates TRAIL-induced apoptosis in glioma via CHOP-dependent DR5 induction. 3244 87